GENE THERAPY IN AIDS

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GENE THERAPY IN AIDS
PRESENTED BY PAIROAJ VONGHATHAIPAISARN MASTER
DEGREE STUDENT OF MAHIDOL UNIVERSITY
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CONTENT
-INTRODUCTION -GENE THERAPY IN MEDICINE -GENE
THERAPY IN AIDS -GENE DELIVERY -CONCLUSION
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GENE THERAPY IS A TREATMENT OR PREVENTION
OF DISEASE BY GENE TRANSFER EDWARD TATUM
GIVE THIS CONCEPT SINCE 1966
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GENE THERAPY IN MEDICINE
-POTENTIAL REVOLUTION IN MECICINE -AIMED AT
TREATING OR ELIMINATING THE CAUSES OF
DISEASE
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GENE THERAPY IN MEDICINE
-ORIGINALLY WAS ENVISIONED AS A MEANS TO
TREAT DISEASES ARISING FROM SINGLE GENE
DEFECTS -FAILURE TO SYNTHESIZE A PARTICULAR
PROTEIN OR TO SYNTHESIS OFF AN ABNORMAL
PROTEIN
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GENE THERAPY IN MEDICINE
-NOW GENE THERAPY ADAPT TO USE IN ACQUIRED
DISEASE SUCH AS AIDS, MALIGNANCIES AND
CARDIOVASCULAR DISEASE -GENE THERAPY FOR
ACQUIRED DISEASE HAS PROCEEDED FASTER THAN
FOR INHERITED DISORDER
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GENE THERAPY IN MEDICINE
-THE EARLIEST HUMAN GENE TRANSFER
EXPERIMENTS BEGAN IN 1989 -NO THERAPEUTIC
EFFECT -SHOWED ONLY SAFETY AND MANY OF
TECHNICAL DIFFICULTIES
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GENE THERAPY IN AIDS
-TODAY, DRUG THERAPY IN AIDS ONLY CONTROL
NOT CURE DISEASE -ADMINISTRATION
SCHEDULES -SIGNIFICANT TOXICITY -SO CONTINUING
NEED FOR NEW OR INNOVATIVE THERAPIES
INCLUDING GENE THERAPY
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GENE THERAPY IN AIDS
1.INTRACELLULAR IMMUNIZATION 2.RIBOZYMES 3.TRANSD
OMINANT MUTANT 4.TROJAN HORSE
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THE HIV LIFE CYCLE AND POINTS OF
INTERVENTION
1.TAT -KEY PLAYER IN THE EARLY STAGES
OF HIV RNA SYNTHESIS 2.REV -SECOND KEY
REGULATOR CAUSES SHIFT IN THE TYPE OF HIV
m RNA PRODUCE TO LONGER TRANSCRIPTS
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BINDING REGION ON TO HIV m RNA -TAT---gt
TAR (TRANS-ACTIVATION RESPONSE-ELEMENT)
-REV-----gt RRE (REV-RESPONSE ELEMENT )
TAT TAR --gtgt POTENT ACTIVATION OF VIRAL
GENE EXPRESSION BY INDUCING TRANSCRIPTIONAL
INITIATION AND ELONGATION REV RRE --gtgt
STRONG ACTIVATES HIV BY FACILITATING THE
EXTRACELLULAR TRANSPORT OF UNSPLICED OR
SINGLY SPLICED m RNA
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RHIBOZYME
RHIBOZYME ARE RNA MOLECULES THAT CONTAIN
ANTISENSE SEQUENCE FOR SPECIFIC RECOGNITION
AND A RNA-CLEAING ENZYMATIC ACTIVITY
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SEVERAL FEATURES OF RZs MAKE THEM
ATTRACTIVE FOR HIV GENE THERAPY
-SIMPLICITY OF DESIGN -LACK OF IMMUNOGENICITY
OF RNA -POSSIBILITY OF DESIGNING MULTIPLE
RZS AGAINST CONSERVED REGION OF VIRAL GENOME
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TWO TYPE OF RZS THAT HAVE BEEN USED
MOST EXTENSIVELY ARE HAIRPIN AND HAMMERHEAD
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HAIRPIN Rz REQUIRING A GUC AT THE CLEVAGE
SITE HAMMERHEAD Rz REQUIRING A NUH (WHERE
N DENOTES ANY BASE AND H DENOTES A, C
OR U)
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RHIBOZYME APPLICATION IN AIDS
TAGET RNA HIV -I Rz TYPE
HAIRPIN HAMMERHEAD MODE OF DELIVERY AND
RESULTING PHENOTYPE RETROVIRUS DELIVERY OF
A VARIETY OF HIV Rzs INHIBITOR VIRAL
REPLICATION 10-1000 FOLD IN T-CELL, T-CELL
LINES AND CD34 STEM CELL PROGENY
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TROJAN HORSE
IS AN ANTI-HIV RNA THAT CONTAINS AN
HIV-PACKAGING SIGNAL COUPLED TO AN ANTI-HIV
NUCLEIC ACID.
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TRANS-DOMIANAT MUTANT (PROTEIN)
TRANSDOMINAT PROTEIN ARE PROTEINS THAT HAVE
ALTERED AMINO ACID THAT RENDER THE MUTANT
PROTEIN CAPABLE OF DISRUPTING THE FUNCTIONS
OF THE WILD-TYPE PROTEIN
LTR
CMV IE
REV M10
LTR
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REGULARTORY PROTEIN TAT, REV STRUCTURAL
PROTEIN Gag AND Env (PREVENT LIBERATION
OF VIRION OR LEAD TO THE RELEASE OF
DEFECTIVE PARTICLES THAT CANNOT INFECT NEW
TARGET CELLS
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INTRACELLULAR IMMUNIZATION (INTRABODIES)
INTRABODY AN ANTIBODY THAT IS PRODUCED
INTRACELLULARY BY GENETIC ENGINEERING TO
MAKE THE ENGINEERED CELLS RESISTANT TO
VIRAL INFECTION
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THESE ARE Ig - DERIVED MOLECULES THAT
COMBINE HIV-SPECIFIC VARIABLE REGIONS WITH
AN ALTERED IMMUNOGLOBULINE CONSTANT REGION
DOMAIN THAT RESULTS IN THE MOLECULES BEING
RETAINED INSIDE THE CELL.
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INTRABODIES AGAINST TAT, REV, REVERSE
TRANSCRIPTASE AND ENVELOPE EPITOPE
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ANOTHER FORM RNA DECOY , SUICIDE GENE,
ANTISENSE NEUCLEIC ACID
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GENE DELIVERY -VIRAL VECTOR -NON VIRAL
VECTOR
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CONCLUSION
THANK YOU VERY MUCH